Coordinate Regulation of TPL-2 and NF-κB Signaling in Macrophages by NF-κB1 p105
Coordinate Regulation of TPL-2 and NF-κB Signaling in Macrophages by NF-κB1 p105
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DOI：
10.1128/mcb.00564-12
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发表时间：
2012-09-01
影响因子：
5.3
通讯作者：
Ley, Steven C.
中科院分区：
文献类型：
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作者：
Yang, Huei-Ting;Papoutsopoulou, Stamatia;Ley, Steven C.
利用Nfkb1(SSAA/SSAA)小鼠巨噬细胞，将p105上的IKK靶位丝氨酸突变为丙氨酸，研究了IKK诱导的核因子-kappaB1p105蛋白分解在天然免疫信号中的作用。我们发现IKK/p105信号通路是细胞外信号调节蛋白(ERK)有丝分裂原激活蛋白(MAP)激酶TPL-2激活所必需的信号转导通路，并调节核因子-kappaB的激活。Nfkb1(SSAA)突变可阻止激动剂诱导的TPL-2从其抑制物p105释放，从而阻断脂多糖(LPS)、肿瘤坏死因子(TNF)、CpG、三棕榈酰半胱氨酸-丝氨酸-赖氨酸(Pam(3)CSK)、PolyI。C)、鞭毛素和R848。Nfkb1(SSAA)突变除了减少relA和cRel的核转位外，还阻止了内毒素诱导的p105向p50的加工，并降低了p50水平。Nfkb1(SSAA/SSAA)巨噬细胞中p50的降低显著降低了内毒素对I kappa B Zeta调节的IL6和CSF2基因的诱导。IL12a和Il12b的内毒素上调也受到损害，尽管TPL-2信号的特异性阻断在晚期时间点增加了这些基因的表达。因此，通过IKK诱导的p105蛋白降解激活TPL-2/ERK信号通路，诱导了一个负反馈环来下调促炎细胞因子IL-12(IL-12)的表达。出乎意料的是，TPL-2不依赖于IKK诱导的p105磷酸化及其激活ERK的能力而促进了可溶性肿瘤坏死因子的产生，这对于开发针对TPL-2的抗炎药物具有重要意义。
The role of I kappa B kinase (IKK)-induced proteolysis of NF-kappa B1 p105 in innate immune signaling was investigated using macrophages from Nfkb1(SSAA/SSAA) mice, in which the IKK target serines on p105 are mutated to alanines. We found that the IKK/p105 signaling pathway was essential for TPL-2 kinase activation of extracellular signal-regulated kinase (ERK) mitogen-activate protein (MAP) kinase and modulated the activation of NF-kappa B. The Nfkb1(SSAA) mutation prevented the agonist-induced release of TPL-2 from its inhibitor p105, which blocked activation of ERK by lipopolysaccharide (LPS), tumor necrosis factor (TNF), CpG, tripalmitoyl-Cys-Ser-Lys (Pam(3)CSK), poly(I . C), flagellin, and R848. The Nfkb1(SSAA) mutation also prevented LPS-induced processing of p105 to p50 and reduced p50 levels, in addition to decreasing the nuclear translocation of RelA and cRel. Reduced p50 in Nfkb1(SSAA/SSAA) macrophages significantly decreased LPS induction of the I kappa B zeta-regulated Il6 and Csf2 genes. LPS upregulation of Il12a and Il12b mRNAs was also impaired although specific blockade of TPL-2 signaling increased expression of these genes at late time points. Activation of TPL-2/ERK signaling by IKK-induced p105 proteolysis, therefore, induced a negative feedback loop to downregulate NF-kappa B-dependent expression of the proinflammatory cytokine interleukin-12 (IL-12). Unexpectedly, TPL-2 promoted soluble TNF production independently of IKK-induced p105 phosphorylation and its ability to activate ERK, which has important implications for the development of anti-inflammatory drugs targeting TPL-2.